Method for electrostatic coating of a medical device

ABSTRACT

A method for electrostatic coating of medical devices such as stents and balloons is described. The method includes applying a composition to a polymeric component of a medical device which has little or no conductivity. The polymeric component could be a material from which the body or a strut of the stent is made or could be a polymeric coating pre-applied on the stent. The polymeric component could be the balloon wall. A charge can then be applied to the polymeric component or the polymeric component can be grounded. Charged particles of drugs, polymers, biobeneficial agents, or any combination of these can then be electrostatically deposited on the medical device or the coating on the medical device. One example of the composition is iodine, iodine, iodide, iodate, a complex or salt thereof which can also impart imaging capabilities to the medical device.

CROSS REFERENCE

This application is a continuation-in-part of U.S. application Ser. No.12/121,692, filed on May 15, 2008, which is now abandoned, and theentire content of U.S. application Ser. No. 12/121,692 is incorporatedby reference.

FIELD OF INVENTION

The present invention is related to methods of electrostatically coatinga medical device, more specifically a stent or a balloon. Moreparticularly, the present invention is related to methods ofelectrostatically depositing drugs or active agents on polymeric stents,polymeric coatings on stents, polymeric dilatation balloons, or othermedical devices.

BACKGROUND OF THE INVENTION

In percutaneous transluminal coronary angioplasty (PTCA), a ballooncatheter is inserted through a brachial or femoral artery, positionedacross a coronary artery occlusion, and inflated to compress againstatherosclerotic plaque to open, by remodeling, the lumen of the coronaryartery. The balloon is then deflated and withdrawn. Problems with PTCAinclude formation of intimal flaps or torn arterial linings, both ofwhich can create another occlusion in the lumen of the coronary artery.Moreover, thrombosis and restenosis may occur several months after theprocedure and create a need for additional angioplasty or a surgicalby-pass operation. To address these issues, stents, which are small,intricate, implantable medical devices, play an important role in PTCA.Stents are generally implanted to reduce occlusions, inhibit thrombosisand restenosis, and maintain patency within vascular lumens such as, forexample, the lumen of a coronary artery.

Stents are often modified to provide drug delivery capabilities tofurther address thrombosis and restenosis. Stents are being coated witha polymeric carrier impregnated with a drug or therapeutic substance. Aconventional method of coating includes applying a composition includinga solvent, a polymer dissolved in the solvent, and a therapeuticsubstance dispersed in the blend to the stent by immersing the stent inthe composition or by spraying the composition onto the stent. Thesolvent is allowed to evaporate, leaving on the stent strut surfaces acoating of the polymer and the therapeutic substance impregnated in thepolymer. However, dipping and spraying techniques requires for largeamounts of drugs and solvents to be used which can be hazardous for theoperator and the environment.

An additional new venue for intravascular therapy is the drug coatedballoon. These devices are dilatation balloons equipped with a drugcontaining coating. This coating consists of a therapeutic drug(s)combined with a polymeric carrier or excipient which may be releasedinto the bloodstream. During peripheral angioplasty, commonly known aspercutaneous transluminal angioplasty (PTA), a balloon dilation isperformed, to dilate an occlusive lesion, with the drug present on theouter coating layer of the balloon. PTA is most commonly used to treatnarrowing of the leg arteries, especially, the iliac, external iliac,superficial femoral and popliteal arteries. PTA can also treat narrowingof veins, and other blood vessels. The drug containing outer coating isthen transferred to the inner wall of the blood vessel. The function ofthe transferred drug coating is to reduce restenosis, or otherundesirable sequelae of the procedure. Drug coated balloons withpaclitaxel are presently approved for use in treatment of the coronaryarteries. However, drug coated balloons are being heavily considered foruse in the peripheral vasculature as shown by the results of the THUNDERand FemPac clinical trials. (Tepe G, et al. N Eng J Med, 358; 7, 2008, p689; Werk M, et al. Circ. 2008; 118: 1358-1365.)

Furthermore, in a study which evaluated restenosis and the rate of majoradverse cardiac events (MACE) such as heart attack, bypass, repeatstenosis, or death in patients treated with drug eluting balloons anddrug eluting stents, the patients treated with drug eluting balloonsexperienced only 3.7 percent restenosis and 4.8 percent MACE as comparedto patients treated with drug eluting stents, in which restenosis was20.8 percent and 22.0 percent MACE rate. (PEPCAD I/II, M. Unverdorben,TCT, October 2007).

One of the putative advantages of PTA balloons is the minimization ofrestenosis after stent implantation. In some PTCA cases, it was foundthat within about six months of stenting, a re-narrowing of the bloodvessel characterized by a growth of smooth muscle cells often persisted.Restenosis was discovered to be a “controlled injury” of the angioplastyprocedure and was analogous to a scar forming over an injury. Drugeluting stents (DES) is one of the solutions to address restenosis bythe use of anti-proliferative and/or cytostatic drugs to interfere withthe vessel cell growth and migration processes.

There are several current theories about the mechanism by which a drugcoated balloon transfers drug to the vessel wall. One theory, forexample, is that upon balloon expansion, drug mechanically fractures ordissolves from the coating, diffuses to the vessel wall and thenpermeates into the vessel wall. A second theory is that upon balloonexpansion the balloon coating is transferred to the vessel wall, andthen drug permeates into the vessel wall from the coating adhered to thevessel wall. Another theory is that the balloon expansion creates tearsand microfissures in the vessel wall and a portion of the coatinginserts into the tears and microfissures. Drug then permeates into thevessel wall from the coating within the tears and fissures. Yet anothertheory is that upon balloon expansion, a layer of dissolved drug andcoating excipients is formed at a high concentration on the vessel wallas a boundary layer. Thus it would be advantageous to have a consistentuniform coating applied to the balloon surface. One that is formulatedto exhibit one of the above properties.

The current dipping and spray techniques are very wasteful methods ofcoating medical devices, most particularly when very small geometricalstructures like stents are being coated. For example, during the sprayapplication of the drug composition, a majority of the coating material,including a drug, is wasted as only a fraction of the spray flux isintercepted by the stent struts. Considering that the pharmaceuticalagents are costly, it would be beneficial to reduce coating processwaste.

Moreover, dipping and spray coating processes can tend to promote agreat deal of coating defects. Coating defects can include an uneventhickness in stent and balloon coating, which would in effect translateinto uneven distribution of the drug across the surface body of themedical device. Stent coating defects can also include “webbing” betweenstent struts (over the gaps or opening between the struts) or coating“pools” which are excessive gatherings on the stent struts. Webbing andpooling can lead to adverse biological responses when the stent isimplanted. A coating process which reduces or eliminates coating defectsand is more superior than the conventional coating processes would bevery desirable.

Finally, dipping and spray coating processes can lead to manufacturinginconsistencies between batches of stents and balloons duringproduction. Lack of control in the coating process can lead to, forexample, an unpredictable drug distribution and inconsistent coatingtopography between different batches of stents or balloons. Anunpredictable drug distribution means that some stents can have moredrug than was intended to be deposited and some can have significantlyless. When coating balloons, a uniform coating is desired in order totreat the vessel uniformly. The possibility of treating the lesion in amore uniform manner is one potential advantage for a drug coated balloonversus a stent. Furthermore, drug transfer from the balloon to thevascular wall tissue and occurs within one minute, and preferably within30 seconds upon inflation of the balloon. Therefore, a need exists forconsistent and uniform drug coating to facilitate efficient drugtransfer to all areas of the vessel wall that is in contact with theballoon surface. A large discrepancy in what was intended to bedeposited is definitely unwanted since it will not be known withaccuracy how much drug a patient will receive. Inconsistent coatingtopography means that the release rate of the drug from stent-to-stentcan vary. Again, it is obviously more desirable to be able to accuratelyprovide, with a very small differential in the mean deviation, theaverage release rate of the drug from the stent or balloon beingmanufactured.

All manufacturers have invested a great amount of research in improvingtheir coating techniques. One proposed method has been by electrostaticdeposition, such as that disclosed in U.S. application Ser. No.11/093,166, to Cameron K. Kerrigan, which is incorporated herein byreference. Electrostatic coating techniques are well known in the art.Particles of a drug are charged. The stent is grounded or is oppositelycharged. The electrostatic attraction between the stent and drug resultsin a more efficient drug deposition, with less waste and more consistentcoating characteristics. This is particularly beneficial for stentswhich have a very complex, three dimensional tubular structure, withstruts separated from each other by gaps. Dilatation balloons,particularly for the peripheral vessels, can be quite large, up to 8×100mm in size. Coating these large medical devices can consume largequantities of drug making an efficient coating process highly desirable.

Stents that are made from metallic materials provide for conductivesurfaces which can be easily charged for electrostatic deposition.However, stents that have been pre-coated with a polymer, for example apolymer primer without a drug, or those that are made from a polymerprovide for electrically non-conductive surfaces and cannot be grounded,biased or polarized for electrostatic deposition of drugs. Furthermore,all dilatation balloons are composed of polymeric materials, and as suchare generally non-conductive. These polymers also cannot be grounded orbiased to allow electrostatic deposition.

The present invention provides for methods of electrostatic coating ofpolymeric stents, stents that include a polymeric coating, or dilatationballoons of insufficient conductivity to be able to efficiently deposita drug or other material.

SUMMARY

A method of manufacturing a drug coated medical device, e.g., stent orballoon, is provided, comprising mounting the device on a supportstructure, the device being made from or including a polymeric materialhaving insufficient conductivity for electrostatic coating; applyingiodine, iodide, iodate, a complex or salt thereof to the surface of thedevice; grounding the device or applying a first charge to the deviceafter the application of the iodine, iodide, iodate, the complex or saltthereof to the surface of the device; and applying a charged drug to thedevice such that the drug is electrostatically deposited on the device.In some embodiments, the amount of iodine, iodide, iodate, the complexor the salt thereof is of an amount that allows for visualization of thestent or balloon by the physician during the procedure. The iodine,iodide, iodate, the complex or salt thereof can be dissolved in asolvent and applied to the surface of the device. The solvent can beremoved prior to the application of the charged drug to the device.Alternatively, the surface of the device is wet during the applicationof the charged drug to the device.

The method can also including applying a charged polymercontemporaneously with the application of the charged drug or prior tothe application of the drug. The drug can be an anti-proliferative orcytostatic agent such as rapamycin, methyl rapamycin, everolimus,42-Epi-(tetrazoylyl)rapamycin (ABT-578), biolimus, temsirolimus,novolimus, myolimus, deforolimus, tacrolimus, paclitaxel, protaxel,taxanes, docetaxel, estradiol, clobetasol, idoxifen, tazarotene and anyprodrugs, metabolites, analogs, homologues, congeners, and anyderivatives, salts and combinations thereof. The therapeutic agents canalso include anti-inflammatory, antineoplastic, antiplatelet,anti-coagulant, anti-fibrin, antithrombotic, antimitotic, antibiotic,antiallergic and antioxidant compounds. Thus, the therapeutic agent canbe, without limitation, a synthetic inorganic or organic compound, aprotein, a peptide, a polysaccharides and other sugars, a lipid, DNA andRNA nucleic acid sequences, an antisense oligonucleotide, an antibody, areceptor ligand, an enzyme, an adhesion peptide, a blood clotting agentincluding streptokinase and tissue plasminogen activator, an antigen, ahormone, a growth factor, a ribozyme, and a retroviral vector.

In accordance with another aspect of the invention, a method of coatinga stent is provided comprising mounting a stent on a support structure,the stent including a polymeric component; applying a treatment materialincluding a halogen, halogen salt, halogen complex or a moiety includinga halide, to the polymeric component; grounding the polymeric componentor applying a charge to the polymeric component; and applying a chargeddrug to the polymeric component such that the drug is electrostaticallydeposited on the stent. The treatment material is iodine, iodide,iodate, a complex or salt thereof. The treatment material can bedissolved in a solvent. In some embodiments, the treatment materialconsists of iodine iodide, iodate, a complex or salt thereof dissolvedin a solvent system. The polymeric component can be the material fromwhich a strut of the stent is made. The polymeric component can bebiodegradable to allow the stent to be eliminated from the patient aftera period of time. The polymeric component can be a coating on thesurface of the stent. In some embodiments, the treatment materialincludes a solvent such that the charged drug is applied only after thesolvent has been removed. Alternatively, the charged drug is appliedprior to the removal of the solvent and when the polymeric component iswet.

In accordance with another aspect of the invention, a method of coatinga balloon is provided comprising mounting a balloon on a support orcontacting element, the balloon including a polymeric component;applying a treatment material including a halogen, halogen salt, halogencomplex or a moiety including a halide, to the polymeric component;grounding the polymeric component or applying a charge to the polymericcomponent; and applying a charged drug to the polymeric component suchthat the drug is electrostatically deposited on the balloon. Thetreatment material is iodine, iodide, iodate, a complex or salt thereof.The treatment material can be dissolved in a solvent. In someembodiments, the treatment material consists of iodine iodide, iodate, acomplex or salt thereof dissolved in a solvent system. The polymericcomponent can be the material from which the balloon is made. Thepolymeric component can be a coating on the surface of the balloon. Insome embodiments, the treatment material includes a solvent such thatthe charged drug is applied only after the solvent has been removed.Alternatively, the charged drug is applied prior to the removal of thesolvent and when the polymeric component is wet.

A medical device may be any suitable substrate that can be implantedpermanently or temporarily in a human or non-human animal. Examples ofmedical devices include, but are not limited to, self-expandable stents,balloon-expandable stents, coronary stents, peripheral stents,stent-grafts, dilatation balloons, angioplasty balloons, catheters,other expandable tubular devices for various bodily lumen or orifices,grafts, vascular grafts, arterio-venous grafts, by-pass grafts,pacemakers and defibrillators, leads and electrodes for the preceding,artificial heart valves, anastomotic clips, arterial closure devices,patent foramen ovale closure devices, cerebrospinal fluid shunts, andparticles (e.g., drug-eluting particles, microparticles andnanoparticles). The stents may be intended for any vessel in the body,including neurological, carotid, vein graft, coronary, aortic, renal,iliac, femoral, popliteal vasculature, and urethral passages. A medicaldevice can be designed for the localized delivery of a therapeuticagent.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an illustration of a stent on a support device beingelectrostatically coated.

FIG. 2 is an illustration of a balloon on distal end of a catheter witha support or contacting element holding the balloon as the balloon isbeing electrostatically coated.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS OF THE INVENTION

A method is provided for electrostatically coating stents having apolymeric component. As illustrated in FIG. 1, a stent 10 is supportedby a mandrel or support structure 20. The mandrel or support structure20 can be coupled to a driving means to provide rotational motion forspinning the stent 10 during electrostatic deposition. In oneembodiment, the stent 10 can have a hollow, tubular body, includingstruts separated by gaps, as best illustrated by reference number 12 and14, respectively. In other embodiments, the stent can be made fromwires, fibers, coiled sheet, with or without gaps, or a scaffoldingnetwork of rings connected by arms. The stent can have any particulargeometrical configuration, such as sinusoidal strut configuration, andshould not be limited to what is illustrated in FIG. 1. The stent can beballoon expandable or self-expandable, both of which are well known inthe art. The stent is preferably for cardiovascular use. In someembodiments, the stent can be for any bodily lumen such as the bileduct, urethra, etc.

The stent can be made from a polymeric material or polymer composites.This means that the struts 12, in and of themselves, are made from apolymer or combination of polymers and excludes any polymeric coatingson the stent. In some embodiments, the stent can be metallic orpolymeric and can include a polymeric coating or polymeric sheath orsleeve in which the stent is inserted. Accordingly, as defined herein, a“polymeric component” is intended to include the whole body of thestent, a part of the body of the stent, the struts, the sleeve/sheath,and/or the coating supported on the stent body substrate. Polymericcomponent, in some embodiments, may include a polymer composite such asfor example a polymer or polymer combination including minor amounts ofa metal such as a bioerodable metal. The coating can be a polymer primerlayer attached to the stent surface and free from any drugs or activeagents. The primer can provide for better adhesion of additional layersof polymers, drugs or other materials. The coating can alternatively bea top-coat layer deposited on a drug reservoir layer to, for example,reduce the rate of release of the drug. The drug reservoir layer can bea polymer free drug layer or can include a combination of a drug andpolymer which have been mixed, blended, bonded or conjugated.

A method is provided for electrostatically coating balloons having apolymeric component. As illustrated in FIG. 2, a balloon 22 on distalend of a catheter 24 is supported by a contact device or support fixture20. The contact or support fixture 20 can be coupled to a driving meansto provide rotational motion for spinning the balloon 22 duringelectrostatic deposition. In one embodiment, the balloon 22 can have aworking length Y and tapers Z. The balloon 22 can have any particulargeometrical configuration, such as cylindrical, tapered, or pleated andshould not be limited to what is illustrated in FIG. 2. The balloon 22itself can be non-compliant or compliant, both of which are well knownin the art. The balloon 22 is preferably for intravascular use. In someembodiments, the balloon 22 can be for any bodily lumen such as the bileduct, urethra, etc.

The balloon 22 can be made from a polymeric material or polymercomposites. As for polymeric material from which the balloon can bemade, preferred examples include polyethylene, polyurethanes,pellethanes, tecoflex, tecothane, silicones, polyesters, Hytrel,polyolefins, polyisobutylene and ethylene-alphaolefin copolymers,acrylic polymers and copolymers other than polyacrylates, vinyl halidepolymers and copolymers (such as polyvinyl chloride), polyvinyl ethers(such as polyvinyl methyl ether), polyvinylidene halides (such aspolyvinylidene chloride), polyacrylonitrile, polyvinyl ketones,polyvinyl aromatics (such as polystyrene), polyvinyl esters (such aspolyvinyl acetate), acrylonitrile-styrene copolymers, ABS resins,polyamides, nylon-6,6, nylon-12, nylon-6, polycaprolactam,poly(amide-co-ether), PEBAX amide-ether copolymer resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, rayon,rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate,cellulose acetate butyrate, cellophane, cellulose nitrate, cellulosepropionate, and cellulose ethers.

In one embodiment, the polymeric material is compliant such as but notlimited to a polyamide/polyether block copolymer (commonly referred toas PEBA or polyether-block-amide). The polyamide and polyether segmentsof the block copolymers may be linked through amide or ester linkages.The polyamide block may be selected from various aliphatic or aromaticpolyamides known in the art. Some non-limiting examples include nylon12, nylon 11, nylon 9, nylon 6, nylon 6/12, nylon 6/11, nylon 6/9, andnylon 6/6. Some non-limiting examples of polyether segments includepoly(tetramethylene ether), tetramethylene ether, polyethylene glycol,polypropylene glycol, poly(pentamethylene ether) and poly(hexamethyleneether). Commercially available PEBA material may also be utilized suchas for example, PEBAX® materials supplied by Arkema (France). Varioustechniques for forming a balloon from polyamide/polyether blockcopolymer is known in the art.

In another embodiment, the balloon material is formed from polyamides.Preferably, the polyamide has substantial tensile strength, be resistantto pin-holing even after folding and unfolding, and be generally scratchresistant, Some non-limiting examples of polyamide materials suitablefor the balloon include nylon 12, nylon 11, nylon 9, nylon 69 and nylon66.

In another embodiment, the balloon may be formed a polyurethanematerial, such as TECOTHANE® (Thermedics). TECOTHANE® is athermoplastic, aromatic, polyether polyurethane synthesized frommethylene disocyanate (MDI), polytetramethylene ether glycol (PTMEG) and1,4 butanediol chain extender. Other suitable compliant polymericmaterials include ENGAGE® (DuPont Dow Elastomers (an ethylenealpha-olefin polymer) and EXACT® (Exxon Chemical), both of which arethermoplastic polymers. Other suitable compliant materials include, butare not limited to, elastomeric silicones, latexes, and urethanes.

The compliant material may be cross linked or uncrosslinked, dependingupon the balloon material and characteristics required for a particularapplication. For example, materials such as the polyolefinic polymersENGAGE® and EXACT®, can be crosslinked. By crosslinking the ballooncompliant material, the final inflated balloon size can be controlled.Conventional crosslinking techniques can be used including thermaltreatment and E-beam exposure. After crosslinking, initialpressurization, expansion, and preshrinking, the balloon will thereafterexpand in a controlled manner to a reproducible diameter in response toa given inflation pressure, and thereby avoid overexpanding the stent(when used in a stent delivery system) to an undesirably large diameter.

In one embodiment, the balloon is formed from a low tensile set polymersuch as a silicone-polyurethane copolymer. Preferably, thesilicone-polyurethane is an ether urethane and more specifically analiphatic ether urethane such as PURSIL AL 575A and PURSIL AL10,(Polymer Technology Group), and ELAST-EON 3-70A, (Elastomedics), whichare silicone polyether urethane copolymers, and more specifically,aliphatic ether urethane cosiloxanes. In an alternative embodiment, thelow tensile set polymer is a diene polymer. A variety of suitable dienepolymers can be used such as but not limited to an isoprene such as anAB and ABA poly(styrene-block-isoprene), a neoprene, an AB and ABApoly(styrene-block-butadiene) such as styrene butadiene styrene (SBS)and styrene butadiene rubber (SBR), and 1,4-polybutadiene. Preferably,the diene polymer is an isoprene including isoprene copolymers andisoprene block copolymers such as poly(styrene-block-isoprene). Apresently preferred isoprene is a styrene-isoprene-styrene blockcopolymer, such as Kraton 1161K available from Kraton, Inc. However, avariety of suitable isoprenes can be used including HT 200 availablefrom Apex Medical, Kraton R 310 available from Kraton, and isoprene(i.e., 2-methyl-1,3-butadiene) available from Dupont Elastomers.Neoprene grades useful in the invention include HT 501 available fromApex Medical, and neoprene (i.e., polychloroprene) available from DupontElastomers, including Neoprene G, W, T and A types available from DupontElastomers.

In some embodiments, the balloon can be composed of multiple layers ofpolymeric materials. Accordingly, as defined herein, a “polymericcomponent” is intended to include the whole body of the balloon, a partof the body of the balloon, the outermost layer of the balloon, and/orthe coating supported on the balloon body substrate. Polymericcomponent, in some embodiments, may include a polymer composite such as,for example, a polymer or polymer combination including minor amounts ofa metal, biodegradable metal, or a reinforcing material. The coating canbe a polymer primer layer attached to the balloon surface and free fromany drugs or active agents. The primer can provide for better adhesionof additional layers of polymers, drugs or other materials. The coatingcan alternatively be a top-coat layer deposited on a drug reservoirlayer to, for example, reduce the rate of release of the drug. The drugreservoir layer can be a polymer free drug layer or can include acombination of the a drug and polymer which have been mixed, blended,bonded or conjugated.

In accordance with another aspect of the invention, the outer surface ofthe medical device including a stent or balloon is physically modified.In this regard, the stent or balloon surface may include a texturedsurface, roughened surface, voids, spines, channels, dimples, pores, ormicrocapsules or a combination thereof. In another embodiment, theballoon includes protrusions configured to contact or penetrate thearterial wall of a vessel upon inflation of the balloon. When inflatedor expanded, a therapeutic agent or coating containing therapeutic agentthat is disposed on the protrusions is penetrated or pushed further intothe tissue of the arterial wall.

The polymeric component can be durable, biodegradable, bioerodable, orbioabsorbable. Biodegradable, bioerodable, and bioabsorbable are termsused interchangeably and refer to polymers that are capable of beingcompletely or substantially degraded or eroded when exposed to an invivo environment or a representative in vitro. A polymeric component iscapable of being degraded or eroded when it can be graduallybroken-down, resorbed, absorbed and/or eliminated by, for example,hydrolysis, enzymolysis, oxidation, metabolic processes, bulk or surfaceerosion, and the like within a subject. In one embodiment, the stent isintended to fully biodegrade, in vivo, with the body of a mammal (e.g.,human), in less than 2 years. In some embodiments, the time frame offull elimination of the stent is from 6 months to 14 months. The humancan be an adult human between the ages of 30 and 85, preferably between40 and 78.

As for polymeric material from which the stent can be made, preferredexamples include poly(N-acetylglucosamine) (Chitin), Chitosan,poly(hydroxyvalerate), poly(lactide-co-glycolide),poly(hydroxybutyrate), poly(hydroxybutyrate-co-valerate),polyorthoester, polyanhydride, poly(glycolic acid), poly(glycolide),poly(L-lactic acid), poly(L-lactide), poly(D,L-lactic acid),poly(L-lactide-co-glycolide); poly(D,L-lactide), poly(caprolactone),poly(trimethylene carbonate), polyethylene amide, polyethylene acrylate,poly(glycolic acid-co-trimethylene carbonate), co-poly(ether-esters)(e.g. PEO/PLA), polyphosphazenes, biomolecules (such as fibrin,fibrinogen, cellulose, starch, collagen and hyaluronic acid),polyurethanes, silicones, polyesters, polyolefins, polyisobutylene andethylene-alphaolefin copolymers, acrylic polymers and copolymers otherthan polyacrylates, vinyl halide polymers and copolymers (such aspolyvinyl chloride), polyvinyl ethers (such as polyvinyl methyl ether),polyvinylidene halides (such as polyvinylidene chloride),polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics (such aspolystyrene), polyvinyl esters (such as polyvinyl acetate),acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides,polyethers, polyurethanes, rayon, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers, andcarboxymethyl cellulose.

Additional representative examples of polymers that may be especiallywell suited for use in fabricating an implantable medical deviceaccording to the methods disclosed herein include ethylene vinyl alcoholcopolymer (commonly known by the generic name EVOH or by the trade nameEVAL), poly(butyl methacrylate), poly(vinylidenefluoride-co-hexafluoropropylene) (e.g., SOLEF 21508, available fromSolvay Solexis PVDF, Thorofare, N.J.), polyvinylidene fluoride(otherwise known as KYNAR, available from ATOFINA Chemicals,Philadelphia, Pa.), ethylene-vinyl acetate copolymers, and polyethyleneglycol.

As for coating materials, preferred examples include, poly(acrylates)such as poly(butyl methacrylate), poly(ethyl methacrylate),poly(hydroxyl ethyl methacrylate), poly(ethyl methacrylate-co-butylmethacrylate), copolymers of ethylene-methyl methacrylate,poly(2-acrylamido-2-methylpropane sulfonic acid), and polymers andcopolymers of aminopropyl methacrylamide, poly(cyanoacrylates),poly(carboxylic acids), poly(vinyl alcohols), poly(maleic anhydride) andcopolymers of maleic anhydride, fluorinated polymers or copolymers suchas poly(vinylidene fluoride), poly(vinylidenefluoride-co-hexafluoropropylene), poly(tetrafluoroethylene), andexpanded poly(tetrafluoroethylene), poly(sulfone), poly(N-vinylpyrrolidone), poly(aminocarbonates), poly(iminocarbonates),poly(anhydride-co-imides), poly(hydroxyvalerate), poly(L-lactic acid),poly(L-lactide), poly(caprolactones), poly(lactide-co-glycolide),poly(hydroxybutyrates), poly(hydroxybutyrate-co-valerate),poly(dioxanones), poly(orthoesters), poly(anhydrides), poly(glycolicacid), poly(glycolide), poly(D,L-lactic acid), poly(D,L-lactide),poly(glycolic acid-co-trimethylene carbonate), poly(phosphoesters),poly(phosphoester urethane), poly(trimethylene carbonate),poly(iminocarbonate), poly(ethylene), poly(propylene)co-poly(ether-esters) such as, for example, poly(dioxanone) andpoly(ethylene oxide)/poly(lactic acid), poly(anhydrides), poly(alkyleneoxalates), poly(phosphazenes), poly(urethanes), silicones, poly(esters),poly(olefins), copolymers of poly(isobutylene), copolymers ofethylene-alphaolefin, vinyl halide polymers and copolymers such aspoly(vinyl chloride), poly(vinyl ethers) such as poly(vinyl methylether), poly(vinylidene halides) such as, for example, poly(vinylidenechloride), poly(acrylonitrile), poly(vinyl ketones), poly(vinylaromatics) such as poly(styrene), poly(vinyl esters) such as poly(vinylacetate), copolymers of vinyl monomers and olefins such aspoly(ethylene-co-vinyl alcohol) (EVAL), copolymers ofacrylonitrile-styrene, ABS resins, and copolymers of ethylene-vinylacetate, poly(amides) such as Nylon 66 and poly(caprolactam), alkydresins, poly(carbonates), poly(oxymethylenes), poly(imides), poly(esteramides), poly(ethers) including poly(alkylene glycols) such as, forexample, poly(ethylene glycol) and poly(propylene glycol), epoxy resins,polyurethanes, rayon, rayon-triacetate, biomolecules such as, forexample, fibrin, fibrinogen, starch, poly(amino acids), peptides,proteins, gelatin, chondroitin sulfate, dermatan sulfate (a copolymer ofD-glucuronic acid or L-iduronic acid and N-acetyl-D-galactosamine),collagen, hyaluronic acid, and glycosaminoglycans, other polysaccharidessuch as, for example, poly(N-acetylglucosamine), chitin, chitosan,cellulose, cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, cellophane, cellulose nitrate, cellulose propionate, celluloseethers, and carboxymethylcellulose, and derivatives, analogs,homologues, congeners, salts, copolymers and combinations thereof. Otherexamples that can be used include polycaprolactones,poly(D,L-lactide-co-PEG) block copolymers,poly(D,L-lactide-co-trimethylene carbonate), polyglycolides,poly(lactide-co-glycolide), poly(amino acids), polycyanoacrylates,poly(trimethylene carbonate) polycarbonates, polyurethanes,copoly(ether-esters) (e.g. PEO/PLA), polyalkylene oxalates, PHA-PEG, andany derivatives, analogs, homologues, salts, copolymers and combinationsthereof.

A treatment composition is applied to the polymeric component. In someembodiments the treatment composition includes a halogen, halide, or acomplex or salt thereof. Iodine, bromine, chlorine and fluorine can beused. In the most preferred embodiment, iodine, iodide, or iodate isused. Complexes of halogen or halides can include those withbiobeneficial polymers such as polyethylene glycol (PEG). PEG is a wellknow bio-friendly polymer that has been reported to have beneficial usewith stents. As another example, poly(N-vinyl pyrrolidone) can be used.Other suitable polymers to use with iodide or iodate salts in stent orballoon coatings are poly(vinyl alcohol), poly(2-hydroxyethylmethacrylate), poly(N-(2-hydroxypropyl)methacrylamide), chitosan,hyaluronic acid, chondroitan sulfate, and poly(ethyleneglycol-co-propylene glycol) copolymers (known as PLURONIC),poly(acrylates) such as poly(butyl methacrylate), poly(ethylmethacrylate), poly(ethyl methacrylate-co-butyl methacrylate),copolymers of ethylene-methyl methacrylate,poly(2-acrylamido-2-methylpropane sulfonic acid), and polymers andcopolymers of aminopropyl methacrylamide, poly(cyanoacrylates),poly(maleic anhydride) and copolymers of maleic anhydride, fluorinatedpolymers or copolymers such as poly(vinylidene fluoride),poly(vinylidene fluoride-co-hexafluoropropylene), poly(sulfone),poly(aminocarbonates), poly(anhydride-co-imides), poly(hydroxyvalerate),poly(L-lactic acid), poly(L-lactide), poly(caprolactones),poly(lactide-co-glycolide), poly(hydroxybutyrates),poly(hydroxybutyrate-co-valerate), poly(dioxanones), poly(orthoesters),poly(anhydrides), poly(glycolic acid), poly(glycolide), poly(D,L-lacticacid), poly(D,L-lactide), poly(glycolic acid-co-trimethylene carbonate),poly(phosphoesters), poly(phosphoester urethane), poly(trimethylenecarbonate), poly(iminocarbonate), poly(ethylene), poly(propylene)co-poly(ether-esters) such as, for example, poly(dioxanone) andpoly(ethylene oxide)/poly(lactic acid), poly(anhydrides), poly(alkyleneoxalates), poly(phosphazenes), poly(urethanes), silicones, poly(esters),poly(olefins), copolymers of poly(isobutylene), copolymers ofethylene-alphaolefin, vinyl halide polymers and copolymers such aspoly(vinyl chloride), poly(vinyl ethers) such as poly(vinyl methylether), poly(vinylidene halides) such as, for example, poly(vinylidenechloride), poly(acrylonitrile), poly(vinyl ketones), poly(vinylaromatics) such as poly(styrene), poly(vinyl esters) such as poly(vinylacetate), copolymers of vinyl monomers and olefins such aspoly(ethylene-co-vinyl alcohol) (EVAL), copolymers ofacrylonitrile-styrene, ABS resins, and copolymers of ethylene-vinylacetate, poly(amides) such as Nylon 66 and poly(caprolactam), alkydresins, poly(carbonates), poly(oxymethylenes), poly(imides), poly(esteramides), poly(ethers) including poly(alkylene glycols) such as, forexample, poly(ethylene glycol) and poly(propylene glycol), epoxy resins,polyurethanes, rayon, rayon-triacetate, biomolecules such as, forexample, fibrin, fibrinogen, starch, poly(amino acids), peptides,proteins, gelatin, chondroitin sulfate, dermatan sulfate (a copolymer ofD-glucuronic acid or L-iduronic acid and N-acetyl-D-galactosamine),collagen, hyaluronic acid, and glycosaminoglycans, other polysaccharidessuch as, for example, poly(N-acetylglucosamine), chitin, chitosan,cellulose, cellulose acetate, cellulose butyrate, cellulose acetatebutyrate, cellophane, cellulose nitrate, cellulose propionate, celluloseethers, and carboxymethylcellulose, and derivatives, analogs,homologues, congeners, salts, copolymers and combinations thereof. Otherexamples that can be used include polycaprolactones,poly(D,L-lactide-co-PEG) block copolymers,poly(D,L-lactide-co-trimethylene carbonate), polyglycolides,poly(lactide-co-glycolide), poly(amino acids), polycarbonates,polyurethanes, copoly(ether-esters) (e.g. PEO/PLA), polyalkyleneoxalates, PHA-PEG, and any derivatives, analogs, homologues, salts,copolymers and combinations thereof. In the case of iodide and iodatesalts, preferred counterions are lithium, sodium, benzalkonium,ammonium, ethanolamine, diethanolamine, imidazole, meglumine,tridodecylmethyl ammonium, cationic lipids, and potassium. Complexes mayalso include non-ionic, anionic, cationic and amphotericsurfactants—which may improve solubility of the halogen.

For a drug coated balloon, the coating can be completely soluble, and assuch, it may contain only biocompatible excipients. Suitable surfactantexcipients to combine with a halogen, halide, or a complex or saltthereof (e.g., iodine, iodide, iodate, salts, etc.) are Tween® 20,Tween® 60, Tween® 80, Vitamin E TPGS, Pluronic F68®, Pluronic F127 ®,Poloxamer 407, Ascorbyl palmitate, gelatin, lecithin, egg yolkphopholipid, phosphatidylcholine, polyethylene glycol-phosphatidylethanolamine conjugate, (PEG-PE), other PEG-Phospholipid conjugates.Other plasticizing components to combine with iodine, iodide, iodate,salts, or complexes, with or without a polymer, are benzyl alcohol,benzyl benzoate, ethanol, DMSO, NMP, glycerol, propylene glycol,Cremophor EL, Vitamin E, Tocopherols, PEG with MW less than 1000, ethyllactate, soybean oil, peanut oil, liquid PEG, poppyseed oil, saffloweroil, vegetable oil, cottonseed oil, castor oil, and almond oil. Halidecontaining compounds are known in the art and readily identifiable byone or ordinary skill in the art.

The treatment composition can be applied in liquid form by immersing thedevice in the treatment composition or spraying the device with thetreatment composition. Brushing techniques can also be used. The liquidform can be accomplished by having a carrier or solvent, for examplewater, an alcohol such as ethanol, isopropanol, and methanol, or anether. The following solvents have been shown to provide acceptable usein coating stents and balloons and can be used with the embodiments ofthe invention: DMAC, DMF, THF, cyclohexanone, xylene, toluene, acetone,methanol, ethanol, i-propanol, n-butanol, methyl ethyl ketone, propyleneglycol monomethyl ether, methyl butyl ketone, ethyl acetate, n-butylacetate, hexane, pentane, octane, and dioxane. A combination of any ofthese can also be used.

The concentration of halogen, halide or halogen (iodine, iodide, iodate,complexes, salts, etc.) containing compound can be from 0.1% to 90%. Itcan be from 1% to 20%. In some embodiments, the halogen or halidecontaining compound, including complexes and salts, is kept on a stentand not washed out. Accordingly, an added benefit can be provided,namely imparting visualization properties to the stent. With the use ofiodine, for example, in one embodiment, the concentration should be highenough to also impart visual capabilities from an imagining device tothe stent (or balloon) when the stent (or balloon) is used in during themedical procedure. Sufficient amount of iodine will allow the physicianto be able to see the stent (or balloon) during delivery andimplantation procedure.

Following the application of the treatment composition, the stent can begrounded (FIG. 1) or a charge can be applied. Charged drug particles 16,having opposite charge or polarity than the stent, should the stent becharged, are then bombarded at the stent. Application by the chargeddrug can be by a nozzle 18 via spray application. FIG. 1 illustrates thedrug being positively charged and the stent grounded. Alternatively anegative charge can be applied to the stent or the drug can benegatively biased or polarized and the stent positively biased orpolarized. The charged drug particles can be applied while the surfaceis wet or dry, or any point in between. In other words, the solvent ofthe treatment composition, if used, can be extracted or semi-extractedsuch as by evaporation before the charged drug particles are applied.

The above described procedure can be similarly followed for a balloon,as illustrated by FIG. 2.

Both liquids and dry powders can be electrostatically coated. The drugcan be in a solvent carrier, such as those mentioned above, or in a dry,powdered form. The present invention is not limited to drugs as otheragents and polymers can be coated using the methods of the presentinvention. In one embodiment, a combination of a polymer and a drug canbe electrostatically coating on the polymeric component of the stent.The polymers can be those previously listed.

As a final step, if opted, a baking treatment can be employed. The stentor balloon can be placed in an oven under suitable temperature that doesnot adversely affect the drug or other components.

Examples of drugs that can be coated on stents using the method of thepresent invention include any moiety capable of contributing to atherapeutic effect, a prophylactic effect, both a therapeutic andprophylactic effect, or other biologically active effect in a mammal. Anagent can also be coated which has a diagnostic property. The drug orbioactive agents include, but are not limited to, small molecules,nucleotides, oligonucleotides, polynucleotides, amino acids,oligopeptides, polypeptides, and proteins. In one example, the drug orbioactive agent inhibits the activity of vascular smooth muscle cells.In another example, the drug or bioactive agent controls migration orproliferation of smooth muscle cells to prevent or inhibit restenosis.

Bioactive agents include, but are not limited to, antiproliferatives,antineoplastics, antimitotics, anti-inflammatories, antiplatelets,anticoagulants, antifibrins, antithrombins, antibiotics, antiallergics,antioxidants, and any prodrugs, metabolites, analogs, homologues,congeners, derivatives, salts and combinations thereof.

Antiproliferatives include, for example, actinomycin D, actinomycin IV,actinomycin I₁, actinomycin X₁, actinomycin C₁, dactinomycin (COSMEGEN®,Merck & Co., Inc.), imatinib mesylate, and any prodrugs, metabolites,analogs, homologues, congeners, derivatives, salts and combinationsthereof. Antineoplastics or antimitotics include, for example,paclitaxel (TAXOL®, Bristol-Myers Squibb Co.), docetaxel (TAXOTERE®,Aventis S. A.), methotrexate, azathioprine, vincristine, vinblastine,fluorouracil, doxorubicin hydrochloride (ADRIAMYCIN®, Pfizer, Inc.) andmitomycin (MUTAMYCIN®, Bristol-Myers Squibb Co.), midostaurin, and anyprodrugs, metabolites, analogs, homologues, congeners, derivatives,salts and combinations thereof.

Antiplatelets, anticoagulants, antifibrin, and antithrombins include,for example, sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors (ANGIOMAX®, Biogen, Inc.), and any prodrugs, metabolites,analogs, homologues, congeners, derivatives, salts and combinationsthereof.

Cytostatic or antiproliferative agents include, for example,angiopeptin, angiotensin converting enzyme inhibitors such as captopril(CAPOTEN® and CAPOZIDE®, Bristol-Myers Squibb Co.), cilazapril orlisinopril (PRINIVIL® and PRINZIDE®, Merck & Co., Inc.); calcium channelblockers such as nifedipine; colchicines; fibroblast growth factor (FGF)antagonists, fish oil (omega 3-fatty acid); histamine antagonists;lovastatin (MEVACOR®, Merck & Co., Inc.); monoclonal antibodiesincluding, but not limited to, antibodies specific for Platelet-DerivedGrowth Factor (PDGF) receptors; nitroprusside; phosphodiesteraseinhibitors; prostaglandin inhibitors; suramin; serotonin blockers;steroids; thioprotease inhibitors; PDGF antagonists including, but notlimited to, triazolopyrimidine; and nitric oxide, and any prodrugs,metabolites, analogs, homologues, congeners, derivatives, salts andcombinations thereof. Antiallergic agents include, but are not limitedto, pemirolast potassium (ALAMAST®, Santen, Inc.), and any prodrugs,metabolites, analogs, homologues, congeners, derivatives, salts andcombinations thereof.

Other bioactive agents that are preferably used in the present inventioninclude, but are not limited to, free radical scavengers; nitric oxidedonors; rapamycin; methyl rapamycin; 42-Epi-(tetrazoylyl)rapamycin(ABT-578); 40-O-(2-hydroxy)ethyl-rapamycin (everolimus); biolimus,myolimus, novolimus, temsirolimus, deforolimus, tacrolimus;pimecrolimus; 40-O-(3-hydroxy)propyl-rapamycin;40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin; tetrazole containingrapamycin analogs such as those described in U.S. Pat. No. 6,329,386;estradiol; clobetasol; idoxifen; tazarotene; alpha-interferon; hostcells such as epithelial cells; genetically engineered epithelial cells;dexamethasone; and, any prodrugs, metabolites, analogs, homologues,congeners, derivatives, salts and combinations thereof.

Free radical scavengers include, but are not limited to,2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical (TEMPO);4-amino-2,2′,6,6′-tetramethyl-1-piperinyloxy, free radical(4-amino-TEMPO); 4-hydroxy-2,2′,6,6′-tetramethyl-piperidene-1-oxy, freeradical (TEMPOL), 2,2′,3,4,5,5′-hexamethyl-3-imidazolinium-1-yloxymethyl sulfate, free radical; 16-doxyl-stearic acid, free radical;superoxide dismutase mimic (SODm) and any analogs, homologues,congeners, derivatives, salts and combinations thereof. Nitric oxidedonors include, but are not limited to, S-nitrosothiols, nitrites,N-oxo-N-nitrosamines, substrates of nitric oxide synthase, diazeniumdiolates such as spermine diazenium diolate and any analogs, homologues,congeners, derivatives, salts and combinations thereof.

Examples of diagnostic agents include radioopaque materials and include,but are not limited to, materials comprising iodine oriodine-derivatives such as, for example, iohexal and iopamidol, whichare detectable by x-rays. Other diagnostic agents such as, for example,radioisotopes, are detectable by tracing radioactive emissions. Otherdiagnostic agents may include those that are detectable by magneticresonance imaging (MRI), ultrasound and other imaging procedures suchas, for example, fluorescence and positron emission tomagraphy (PET).Examples of agents detectable by MRI are paramagnetic agents, whichinclude, but are not limited to, gadolinium chelated compounds. Examplesof agents detectable by ultrasound include, but are not limited to,perflexane. Examples of fluorescence agents include, but are not limitedto, indocyanine green. Examples of agents used in diagnostic PETinclude, but are not limited to, fluorodeoxyglucose, sodium fluoride,methionine, choline, deoxyglucose, butanol, raclopride, spiperone,bromospiperone, carfentanil, and flumazenil.

From the foregoing detailed description, it will be evident that thereare a number of changes, adaptations and modifications of the presentinvention which come within the province of those skilled in the art.The scope of the invention includes any combination of the elements fromthe different species or embodiments disclosed herein, as well assubassemblies, assemblies, and methods thereof. However, it is intendedthat all such variations not departing from the spirit of the inventionbe considered as within the scope thereof.

1. A method of manufacturing a drug coated stent, comprising: mounting astent on a support structure, the stent being made from a biodegradablepolymeric material having insufficient conductivity for electrostaticcoating, wherein the stent fully degrades in vivo, in a mammaliansubject, within 2 years; applying iodine, iodide, iodate, a complex orsalt thereof to the surface of the stem; applying a first charge to thestent after the application of the iodine, iodide, iodate, the complexor salt thereof to the surface of the stent; and applying a drug havinga charge to the stent such that the drug is electrostatically depositedon the stent.
 2. The method of claim 1, wherein the stent fully degradesin vivo, in a mammalian subject, within 6 months to 14 months.
 3. Themethod of claim 1, wherein the iodine, iodide, iodate, the complex orsalt thereof remains on the stent and the amount remaining on the stentallows for visualization of the stent by a physician during a stentimplantation procedure.
 4. The method of claim 1, wherein the iodine,iodide, iodate, the complex or salt thereof is dissolved in a solventand applied to the surface of the stent.
 5. The method of claim 4,wherein the solvent is removed prior to the application of the chargeddrug to the stent.
 6. The method of claim 4, wherein the surface of thestent is wet during the application of the charged drug to the stent. 7.The method of claim 1, additionally comprising applying a chargedpolymer contemporaneously with the application of the charged drug. 8.The method of claim 1, wherein the drug is selected from the groupconsisting of rapamycin, methyl rapamycin, everolimus,42-Epi-(tetrazoylyl)rapamycin (ABT-578), biolimus, temsirolimus,myolimus, novolimus, deforolimus, tacrolimus, paclitaxel, protaxel,docetaxel, estradiol, clobetasol, idoxifen, tazarotene, and combinationsthereof.
 9. The method of claim 1, additionally comprising rotating thesupport structure to rotate the stent during electrostatic deposition ofthe drug.
 10. A method of manufacturing a drug coated balloon,comprising: mounting a balloon on a support structure, the balloon beingmade from a polymeric material having insufficient conductivity forelectrostatic coating; applying iodine, iodide, iodate, a complex orsalt thereof to a surface of the balloon; applying a first charge to theballoon after the application of the iodine, iodide, iodate, the complexor salt thereof to the surface of the balloon; and applying a drughaving a charge to the balloon such that the drug is electrostaticallydeposited on the balloon.
 11. The method of claim 10, wherein theiodine, iodide, iodate, the complex or salt thereof remains on theballoon and the amount remaining on the balloon allows for visualizationof the balloon by a physician during a balloon dilatation procedure. 12.The method of claim 10, wherein the iodine, iodide, iodate, the complexor salt thereof is dissolved in a solvent and applied to the surface ofthe balloon.
 13. The method of claim 12, wherein the solvent is removedprior to the application of the charged drug to the balloon.
 14. Themethod of claim 12, wherein the surface of the balloon is wet during theapplication of the charged drug to the balloon.
 15. The method of claim10, additionally comprising applying a charged polymer contemporaneouslywith the application of the charged drug.
 16. The method of claim 10,wherein the drug is selected from the group consisting of rapamycin,methyl rapamycin, everolimus, 42-Epi-(tetrazoylyl)rapamycin (ABT-578),biolimus, temsirolimus, myolimus, novolimus, deforolimus, tacrolimus,paclitaxel, protaxel, docetaxel, estradiol, clobetasol, idoxifen,tazarotene and combinations thereof.
 17. The method of claim 10,additionally comprising applying a surfactant excipient with the iodine,iodide, iodate, the complex or salt thereof.